PROJECT DESCRIPTION This project addresses patients' recovery from stroke and the development of post-stroke dementia, a sub- category of vascular dementia that affects approximately one-third of stroke sufferers. Following stroke, the blood brain barrier (BBB) is breached in the area of the lesion. As part of a cellular repair response, reactive astrocytes join together via an unknown mechanism to form a physical barrier to seal off the damaged area and protect the surviving neuropil. Astrogliosis and the formation of the glial scar is a critical component of the healing response to stroke. However, there have been no studies on the possibility that failure of the glial scar to perfectly seal the area of injury, which we recently demonstrated is also a site of chronic inflammatory responses, contributes to cognitive decline in patients that develop post-stroke dementia. This limitation has been due, in part, to the lack of an effective animal model of delayed cognitive dysfunction following stroke. However, we recently developed an innovative new mouse model of delayed cognitive dysfunction following stroke that models hallmarks of post-stroke dementia. Using this model, we now have substantial evidence that failure of the glial scar to segregate chronically leaky blood vessels within the lesion, as well as chronic inflammatory responses occurring in the lesion, is one cause of post-stroke dementia. Therefore the goals of this project are to determine for the first time precisely how (and how effectively) the glial scar seals the area of injury following stroke, by identifying the cellular and molecular mechanisms involved, and then to manipulate these mechanisms to enhance repair by the glial scar. These goals will be achieved by using our new mouse model of delayed cognitive dysfunction following stroke in conjunction with confocal and electron microscopy, immunohistochemistry, biochemical assays, flow cytometry, multiplex immunoassays, and behavioral studies, in adult and aged wildtype and transgenic mice. At the end of these studies we will have revealed how well the glial scar seals lesions following stroke in both adult and aged mice, interrogated a key pathway involved in glial scar regulation for which there is little data, and pharmacologically manipulated this pathway to improve the barrier function of the glial scar, and thereby protect against the development of post-stroke dementia.